Abstract:
:High-dose radiation activates caspases in tumor cells to produce abundant DNA fragments for DNA sensing in antigen-presenting cells, but the intrinsic DNA sensing in tumor cells after radiation is rather limited. Here we demonstrate that irradiated tumor cells hijack caspase 9 signaling to suppress intrinsic DNA sensing. Instead of apoptotic genomic DNA, tumor-derived mitochondrial DNA triggers intrinsic DNA sensing. Specifically, loss of mitochondrial DNA sensing in Casp9-/- tumors abolishes the enhanced therapeutic effect of radiation. We demonstrated that combining emricasan, a pan-caspase inhibitor, with radiation generates synergistic therapeutic effects. Moreover, loss of CASP9 signaling in tumor cells led to adaptive resistance by upregulating programmed death-ligand 1 (PD-L1) and resulted in tumor relapse. Additional anti-PD-L1 blockade can further overcome this acquired immune resistance. Therefore, combining radiation with a caspase inhibitor and anti-PD-L1 can effectively control tumors by sequentially blocking both intrinsic and extrinsic inhibitory signaling.
journal_name
Nat Immunoljournal_title
Nature immunologyauthors
Han C,Liu Z,Zhang Y,Shen A,Dong C,Zhang A,Moore C,Ren Z,Lu C,Cao X,Zhang CL,Qiao J,Fu YXdoi
10.1038/s41590-020-0641-5subject
Has Abstractpub_date
2020-05-01 00:00:00pages
546-554issue
5eissn
1529-2908issn
1529-2916pii
10.1038/s41590-020-0641-5journal_volume
21pub_type
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abstract:: ...
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